TRPV1 ion channels play a critical role in the increase in sensitivity to pain that occurs in the setting of inflammation in the cornea and throughout the peripheral nervous system. We address the cellular and molecular mechanisms by which one of the most important inflammatory mediators, nerve growth factor (NGF), triggers trafficking of TRPV1 to the plasma membrane. We have previously shown that NGF increases the number of TRPV1 channels in the plasma membrane of sensory neurons via activation of the enzyme phosphoinositide 3-kinase (PI3K, Class IA), which phosphorylates the signaling lipid phosphoinositide 4,5-bisphosphate (PIP2) to make phosphoinositide 3,4,5-trisphosphate (PIP3) (Figure 1A). PIP3 is a ubiquitous signal for membrane trafficking, and causes TRPV1-laden vesicles to fuse with the plasma membrane via regulated exocytosis. This enhanced trafficking is facilitated by a direct interaction among the Ankyrin Repeat Domain (ARD) of TRPV1 and the p85 regulatory subunit of PI3K (Figure 1B). The major preliminary finding upon which this renewal proposal is based is that the interaction between TRPV1 and PI3K potentiates NGF-stimulated activation of PI3K. This proposal will leverage our preliminary data to investigate the physiology and mechanism by which this occurs.
Developing new forms of on-opiate pain relief should be a high priority in our aging population, yet a major barrier is our lack of basic understanding of pain signaling at the level of cells and receptors. This proposal uses state-of-the-art tools to probe the molecular and cellular mechanisms responsible for acute inflammatory pain due to trafficking of TRPV1 ion channels to the surface of pain-transducing neurons.
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